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. 2023 May 4;10(6):ofad225.
doi: 10.1093/ofid/ofad225. eCollection 2023 Jun.

Participant- and Disease-Related Factors as Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Clinical Trial: A Multivariable Regression Analysis

Ignacio Martin-Loeches  1 , Andrew F Shorr  2 , Marin H Kollef  3 , Jiejun Du  4 , Maria C Losada  4 , Amanda Paschke  4 , C Andrew DeRyke  4 , Michael Wong  4 , Erin H Jensen  4 , Luke F Chen  4
Affiliations

Participant- and Disease-Related Factors as Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Clinical Trial: A Multivariable Regression Analysis

Ignacio Martin-Loeches et al. Open Forum Infect Dis. .

Abstract

Background: In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making.

Methods: A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment.

Results: Vasopressor use, renal impairment, bacteremia at baseline, and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores ≥15 were associated with a greater risk of day 28 ACM. A favorable clinical response at EFU was associated with normal renal function, an APACHE II score <15, no vasopressor use, and no bacteremia at baseline. At EOT, a favorable microbiologic response was associated with IMI/REL treatment, normal renal function, no vasopressor use, nonventilated pneumonia at baseline, intensive care unit admission at randomization, monomicrobial infections at baseline, and absence of Acinetobacter calcoaceticus-baumannii complex at baseline. These factors remained significant after accounting for polymicrobial infection and in vitro susceptibility to assigned treatment.

Conclusions: This analysis, which accounted for baseline pathogen susceptibility, validated well-recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL.

Clinical trials registration: NCT02493764.

Keywords: HABP; VABP; antibiotic; imipenem; relebactam.

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Conflict of interest statement

Potential conflicts of interest. L. F. C., J. D., M. C. L., A. P., C. A. D., M. W., and E. H. J. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, who may own stock and/or hold stock options in the Merck & Co, Inc, Rahway, New Jersey. All other authors report no potential conflicts.

Figures

Figure 1.
Figure 1.
Odds ratio estimates for day 28 all-cause mortality in the modified intent-to-treat (MITT) population (A) and the microbiologic MITT (mMITT) population (B). The mMITT population includes polymicrobial infection and susceptibility to assigned treatment. aNormal renal function is creatinine clearance ≥90 to <150 mL/min. Abbreviations: ACM, all-cause mortality; APACHE, Acute Physiologic Assessment and Chronic Health Evaluation; ARC, augmented renal clearance; CI, confidence interval; RI, renal impairment.
Figure 2.
Figure 2.
Odds ratio estimates for favorable clinical response at end of follow-up in the modified intent-to-treat (MITT) population (A) and the microbiologic MITT population (mMITT) (B). The mMITT population includes polymicrobial infection and susceptibility to assigned treatment. aNormal renal function is creatinine clearance ≥90 to <150 mL/min. Abbreviations: APACHE, Acute Physiologic Assessment and Chronic Health Evaluation; ARC, augmented renal clearance; CI, confidence interval; CR, clinical response; EFU, end of follow-up; RI, renal impairment.
Figure 3.
Figure 3.
Odds ratio estimates for overall favorable MR at end of treatment in the microbiologic modified intent-to-treat population (A) and the susceptibility-sensitivity analysis (B). The susceptibility-sensitivity analysis accounts for susceptibility to assigned treatment for causative pathogens. aNormal renal function is creatinine clearance ≥90 to <150 mL/min. Abbreviations: ARC, augmented renal clearance; CI, confidence interval; EOT, end of treatment; HABP, hospital-acquired bacterial pneumonia; ICU, intensive care unit; IMI/REL, imipenem/cilastatin/relebactam; MR, microbiologic response; PIP/TAZ, piperacillin/tazobactam; RI, renal impairment.
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